Hepatitis C virus (HCV) infection is more frequent in veterans than in nonveterans. Up to 85% of HCV-infected veterans have psychiatric and/or substance use (SU) co-morbidities which, prior to the 2002 NIH Consensus Conference, were considered relative contraindications to antiviral therapy, assuming a poor adherence. With the objective of evaluating the validity of this assumption, we compared eligibility, completion and response to antiviral therapy in HCV-infected veterans with and without these comorbidities. Veterans who were anti-HCV-positive and had been seen at least once in the liver clinic (between October 1999 and June 2002) were identified through the CT-VAHCS database. Records were reviewed for patient demographics and status of liver disease, assessment of treatment eligibility, type of therapy, completion of therapy and virological response. Patients with active mental illness (MI) or SU were compared with those without these comorbidities (controls). Of 697 anti-HCV-positive-patients, 647 HCV-RNA-positive patients were included, 294 with MI/SA and 353 controls. Patient demographics, viral and liver disease characteristics were comparable between groups. Patients with MI/SA were considered ineligible for therapy more frequently (53%vs 39%, P < 0.001) and were treated less frequently (21%vs 28%, P = 0.03) than controls. However, completion of therapy (72%vs 59%) and sustained virological response (SVR) (20%vs 25%) did not differ significantly between groups. HCV-infected veterans with MI/SA are being offered therapy and treated less often than those without such co-morbidities, however therapy completion and SVR rates are similar, challenging the perception that adherence is poorer in this patient population.